The in vivo release of IL-1 from monocytes stimulated by exposure to bacteria or their products is pivotal to the generation of the acute-phase immune response following infection. The physiological and pathogenic responses of organs and tissues to IL-1 have been extensively reviewed, e.g. Dinarello, Rev. Infect. Dis., Vol. 6, pgs. 51-95 (1984). From an immunological standpoint, monocyte-derived IL-1 is crucial to host defense since triggering of both humoral and cell mediated branches of the immune system appear to be dependent upon its synthesis. IL-1 mediates a wide range of biological activities including stimulation of thymocyte proliferation via induction of interleukin-2 (IL-2) release, stimulation of B-lymphocyte maturation and proliferation, fibroblast growth factor activity and induction of acute-phase protein synthesis by hepatocytes. IL-1 has also been reported to stimulate prostaglandin and collagenase release from synovial cells, and to be identical to endogenous pyrogen, Krampschmidt, J. Leuk. Biol., Vol. 36, pgs. 341-355 (1984).
Biochemical and cDNA cloning studies have defined two related IL-1 proteins (.alpha. and .beta.) that appear to have similar activities, March et al., "Cloning, Sequence and Expression of Two Distinct Human Interleukin-1 Complementary DNAs," Nature, Vol. 315, pgs. 641-647 (1985) and Gubler et al., "Recombinant Human Interleukin-1.alpha.: Purification and Biological Characterization," J. Immunol., Vol. 136, pgs. 2492-2497 (1986). The primary translation products of IL-1.alpha. and IL-1.beta. mRNAs are, respectively, 271 and 269 amino acid proteins that do not encode typical transmembrane signal sequences (March et al., cited above). IL-1 appears to be a C-terminal 17,500 dalton fragment of the primary translation product, and expression of this fragment in E. coli produces a protein with properties apparently identical to the natural protein (March et al., and Gubler et al, cited above).
It is believed that IL-1, either alone or in combination with other lymphokines, has potential clinical applications, e.g. Sorg et al., Eds. Cellular and Molecular Biology of Lymphokines (Academic Press, New York, 1985). The development of a highly efficient bacterial expression system for IL-1 would increase its availability for medical and research applications, and the development of a rapid and convenient method of manipulating the amino acid sequence of native IL-1.alpha. would facilitate the development of useful IL-1.alpha. muteins.